|Publication number||US4853371 A|
|Application number||US 07/209,883|
|Publication date||Aug 1, 1989|
|Filing date||Jun 22, 1988|
|Priority date||Jun 17, 1986|
|Publication number||07209883, 209883, US 4853371 A, US 4853371A, US-A-4853371, US4853371 A, US4853371A|
|Inventors||David H. Coy, William A. Murphy, Mark L. Heiman|
|Original Assignee||The Administrators Of The Tulane Educational Fund|
|Export Citation||BiBTeX, EndNote, RefMan|
|Patent Citations (10), Non-Patent Citations (5), Referenced by (110), Classifications (18), Legal Events (6) |
|External Links: USPTO, USPTO Assignment, Espacenet|
Therapeutic somatostatin analogs
US 4853371 A
An octapeptide of the formula: ##STR1## wherein each A1 and A2, independently, is H, C1-12 alkyl, C7-10 phenylalkyl, R1 CO (where R1 is C1-20 alkyl, C3-20 alkenyl, C3-20 alkinyl, phenyl, naphthyl, or C7-10 phenylalkyl, R2 OCO (where R2 is C1-10 alkyl or C7-10 phenylalkyl), provided that when one of A1 or A2 is R1 CO or R2 OCO, the other must be H; A3 is CH2 -A6 (where A6 is pentafluorophenyl, naphthyl, pyridyl, or phenyl); A4 is o- m- or p-substituted X-Phe (where X is a halogen, H, NO2, OH, NH2, or C1-3 alkyl), pentafluoro-Phe, or α-Nal; A5 is Thr, Ser, Phe, Val, α-aminobutyric acid, or Ile, provided that when A3 is phenyl, A1 is H, and A2 is H, A5 cannot be Val; and A7 is Thr, Trp, or β-Nal; or a pharmaceutically acceptable salt thereof.
1. An octapeptide of the formula D-β-Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2, or a pharmaceutically acceptable salt thereof.
2. The octapeptide of claim 1 of the formula D-Phe-Cys-β-Nal-D-Trp-Lys-Val-Cys-Thr-NH2.
3. A therapeutic composition capable of inhibiting the release of growth hormone, insulin, glucagon, or pancreatic exocrine secretion comprising a therapeutically effective amount of the compound of claim 1 together with a pharmaceutically acceptable carrier substance.
4. A method of treating a mammal in need of reduction of growth hormone, insulin, glycagon, or pancreatic exocrine secretion comprising administering to said mammal a therapeutically effective amount of the compound of claim 1.
5. The therapeutic composition of claim 3 wherein said composition is in the form of a pill, tablet, or capsule for oral administration to a human patient in need of said compound.
6. The therapeutic composition of claim 3 wherein said composition is in the form of a liquid for oral administration to a human patient in need of said compound.
7. The therapeutic composition of claim 5, said composition being coated with a substance capable of protecting said composition from the gastric acid in the stomach of said human patient for a period of time sufficient to allow said composition to pass undisintegrated into the small intestine of said human patient.
8. The therapeutic composition of claim 3, said composition being in the form of a cream, gel, spray, or ointment for application to the skin of a human patient in need of said compound.
9. The therapeutic composition of claim 3, said composition being in the form of a liquid capable of being administered nasally as drops or spray to a human patient in need of said compound.
10. The therapeutic composition of claim 3, said composition being in the form of a liquid for intravenous, subcutaneous, parenteral, or intraperitioneal administration to a human patient in need of said compound.
11. The therapeutic composition of claim 3, said composition being in the form of a biodegradable sustained release composititon for intramuscular administration to a human patient in need of said compound.
BACKGROUND OF THE INVENTION
This application is a continuation in part of Coy et al. U.S. Ser. No. 070,400, filed July 7, 1978, now abandoned, which in a continuation in part of Coy et al. U.S. Ser. No. 010,349, filed Feb. 3, 1987, which is a continuation in part of Coy et al. U.S. Ser. No. 875,266, filed June 17, 1986, now abandoned, which is a continuation in part of Coy et al. U.S. Ser. No. 775,488, filed Sept. 12, 1985, now abandoned.
This invention relates to therapeutic peptides.
A number of somatostatin analogs exhibiting GH-release-inhibiting activity have been described in the literature, including analogs containing fewer than the naturally occurring fourteen amino acids. For example, Coy et al. U.S. Pat. No. 4,485,101, hereby incorporated by reference, describes dodecapeptides having an N-terminal acetyl group, a C-terminal NH2, D-Trp at position 6, and p-Cl-Phe at position 4. (Herein, when no designation of configuration is given, the L-isomer is intended.)
SUMMARY OF THE INVENTION
In general, the invention features an octapeptide of the formula: ##STR2## wherein each A1 and A2, independently, is H, C1-12 alkyl, C7-10 phenylalkyl, R1 CO (where R1 is C1-20 alkyl, C3-20 alkenyl, C3-20 alkinyl, phenyl, naphthyl, or C7-10 phenylalkyl), or R2 OCO (where R2 is C1-10 alkyl or C7-10 phenylalkyl), provided that when one of A1 or A2 is R1 CO or R2 OCO, the other must be H; A3 is CH2 -A6 (where A6 is pentafluorophenyl, naphthyl, pyridyl, phenyl, or o-, m-, or, more preferably, p-substituted phenyl, where the substituent is a halogen, NH2, NO2, OH, or C1-3 alkyl); A4 is o-, m-, or, more preferably, p-substituted X-Phe (where X is a halogen, H, NH2, NO2, OH, or C1-3 alkyl), pentafluoro-Phe, or β-Nal; A5 is Thr, Ser, Phe, Val, α-aminobutyric acid, or Ile, provided that when A3 is phenyl, A1 is H, and A2 is H, A5 cannot be Val; and A7 is Thr, Trp, or β-Nal; or a pharmaceutically acceptable salt thereof.
In the formula given above, the configuration of the molecule at the carbon atom to which A3 is bonded is not given, to indicate that the amino acid residue of which A3 is a substituent can have the D- or L-configuration. In the formula given above, there is a bond shown between the two Cys residues to indicate cyclization; in all of the compounds of the invention there is such cyclization, but the Cys--Cys bond lines are omitted for convenience.
Preferred compounds of the invention include D-β-Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2 ; D-Phe-Cys-Tyr-D-Trp-Lys-α-Aminobutyric acid-Cys-Thr-NH2 ; pentafluoro-D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2 ; N-Ac-D-β-Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2 ; D-β-Nal-Cys-pentafluoro-Phe-D-Trp-Lys-Val-Cys-Thr-NH2 ; D-β-Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-β-Nal-NH2 ; D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-β-Nal-NH2 ; D-β-Nal-Cys-Tyr-D-Trp-Lys-α-aminobutyric acid-Cys-Thr-NH2 ; D-p-Cl-Phe-Cys-Tyr-D-Trp-Lys-α-aminobutyric acid-Cys-Thr-NH2 ; and acetyl-D-p-Cl-Phe-Cys-Tyr-D-Trp-Lys-α-aminobutyric acid-Cys-Thr-NH2 ; and D-Phe-Cys-β-Nal-D-Trp-Lys-Val-Cys-Thr-NH2.
In other preferred embodiments, a therapeutically effective amount of the therapeutic compound and a pharmaceutically acceptable carrier substance (e.g. magnesium carbonate, lactose, or a phospholipid with which the therapeutic compound can form a micelle). The most preferred carried substance is mannitol. Examples of such compositions include a pill, tablet, capsule, or liquid for oral administration to a human patient, a spreadable cream, gel, lotion, or ointment for application to the skin of a human patient in need of the compound, a liquid capable of being administered nasally as drops or spray, or a liquid capable of intravenous, parenteral, subcutaneous, or intraperitoneal administration. The pill, tablet or capsule can be coated with a substance capable of protecting the composition from the gastric acid in the patient's stomach for a period of time sufficient to allow the composition to pass undisintegrated into the patient's small intestine. The therapeutic composition can also be administered in the form of an oil emulsion or dispersion in conjunction with a lipophillic salt such as a pamoic acid. The therapeutic composition can also be in the form of a biodegradable sustained release formulation for intramuscular administration. For maximum efficacy, zero order release is desired. Zero order release can be obtained using an implantable or external pump, e.g., Infusaid™ pump, to administer the therapeutic composition.
The compounds of the invention are active in inhibiting the secretion of GH, insulin, and glucagon. Further, the aromatic lipophilic N-terminal end can provide long-lasting in vivo activity.
Other features and advantages of the invention will be apparent from the following description of the preferred embodiments thereof, and from the claims.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The compounds of the invention have the general formula recited in the Summary of the Invention, above. They are all octapeptide analogs of somatostatin which have D-Trp at position 4; and optional modifications at positions 3(A4) 6(A5) and 8(A7). It has been found that D-β-naphthylalanine at positions 1 and/or 3; Tyr at position 3; and Val at position 6 are modifications which particularly enhance activity.
The compounds can be provided in the form of pharmaceutically acceptable salts or complexes. Examples of preferred salts or complexes are those with therapeutically acceptable organic acids, e.g., acetic, lactic, maleic, citric, malic, ascorbic, succinic, benzoic, salicylic, methanesulfonic, toluenesulfonic, or pamoic acid, as well as polymeric acids such as tannic acid or carboxymethyl cellulose, and salts with inorganic acids such as the hydrohalic acids, e.g., hydrochloric acid, sulfuric acid, or phosphoric acid.
The synthesis of one octapeptide follows. Other octapeptides of the invention can be prepared by making appropriate modifications, within the ability of someone of ordinary skill in this field, of the following synthetic method.
The first step in the preparation of D-β-naphthylalanine-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2 was the preparation of the intermediate tert-butyloxycarbonyl-D-β-naphthylalanine-S-methylbenzyl-Cys-Tyr-D-Trp-N68 -benzyloxycarbonyl-Lys-Val-S-methylbenzyl-Cys-O-benzyl-Thr-benzyhydrylamine resin, as follows.
Benzhydrylamine-polystyrene resin (Vega Biochemicals, Inc.) in the chloride ion form was placed in the reaction vessel of a Beckman 990B peptide synthesizer programmed to perform the following reaction cycle: (a) methylene chloride: (b) 33% trifluoroacetic acid in methylene chloride (2 times for 1 and 25 min each); (c) methylene chloride; (d) ethanol; (e) methylene chloride; (f) 10% triethylamine in chloroform.
The neutralized resin was stirred with Boc-O-benzyl-threonine and diisopropylcarbodiimide (1.5 mmole each) in methylene chloride for 1 h and the resulting amino acid resin was then cycled through steps (a) to (g) in the above wash program. The following amino acids (1.5 mmole) were then coupled successively by the same procedure: Boc-S-methylbenzyl-Cys, Boc-Val, Boc-Ne-benzyloxycarbonyl-lysine, Boc-D-Trp, Boc-Tyr, Boc-S-methylbenzyl-Cys, Boc-D-β-naphthylalanine.
The resin was washed and dried and then mixed with anisole (4 ml) and anhydrous hydrogen fluoride (36 ml) at 0° C. and stirred for 45 min. (one can also use thioanisole, trifluoroacetic acid, and trifluoromethane sulfonic acid at a ratio of 1:90:9, for 6 h). Excess hydrogen fluoride was evaporated rapidly under a stream of dry nitrogen and free peptide precipitated and washed with ether. The crude peptide was then dissolved in 800 ml of 90% acetic to which was added I2 in methanol until a permanent brown color was present. The solution was then stirred for 1 h before removing the solvent in vacuo. The resulting oil was dissolved in a minimum volume of 50% acetic acid and eluted on a column (2.5×100 mm) of Sephadex G-25. Fractions containing a major component by uv absorption and thin layer chromatography were then pooled, evaporated to a small volume, and applied to a column (2.5×50 cm) of Whatman LRP-1 octadecylsilane (15-20 μM).
The column was eluted with a linear gradient of 10-50% acetonitrile in 0.1% trifluoroacetic acid in water. Fractions were examined by thin layer chromatography and analytical high performance liquid chromatography and pooled to give maximum purity and if desired, a different salt prepared, e.g., acetate or phosphate. Repeated lyophilization of the solution from water gave 170 mg of the product as a white, fluffy powder.
The product was found to be homogeneous by Hplc and Tlc. Amino acid analysis of an acid hydrolysate confirmed the composition of the octapeptide.
The octapeptides of the invention having the formulae pentafluoro-D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2, D-Phe-Cys-Tyr-D-Trp-Lys-α-aminobutyric acid-Cys-Thr-NH2, N-Ac-D-β-Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2, D-β-Nal-Cys pentafluoro-Phe-D-Trp-Lys-Val-Cys-Thr-NH2, D-β-Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-β-Nal-NH2, D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-β-Nal-NH2 ; D-β-Nal-Cys-Tyr-D-Trp-Lys-α-aminobutyric acid-Cys-Thr-NH2 ; D-p-Cl-Phe-Cys-Tyr-D-Trp-Lys-α-aminobutyric acid-Cys-Thr-NH2 ; acetyl-D-p-Cl-Phe-Cys-Tyr-D-Trp-Lys-α-aminobutyric acid-Cys-Thr-NH2 ; and D-Phe-Cys-β-Nal-D-Trp-Lys-Val-Cys-Thr-NH2 were made according to methods analogous to those described above.
When administered to mammals, particularly humans, (e.g. orally, topically, intravenously, parenterally in a sustained release, biodegradable form, nasally, or by suppository), the compounds can be effective to inhibit GH release as well as to inhibit insulin, glucagon, and pancreatic exocrine secretion, and to therapeutically affect the central nervous system.
The compounds can be administered to a mammal, e.g. a human, in the dosages used for somatostatin or, because of their greater potency, in smaller dosages. The compounds of the invention can be used for the treatment of cancer, particularly growth hormone-dependent cancer (e.g., bone, cartilage, pancreas (endocrine and exocrine), prostate, or breast), acromegaly and related hypersecretroy endocrine states, or of bleeding ulcers in emergency patients and in those suffering from pancreatitis or diarrhea. The compounds can also be used in the management of diabetes and to protect the liver of patients suffering from cirrhosis or hepatitis. The compounds can also be used to treat Alzheimer's disease, as analgesics to treat pain by acting specifically on certain opiate receptors, and as gastric cytoprotective compounds for ulcer therapy. The compounds can also be used to treat certain types of mushroom poisoning.
The compounds can also be used to treat diabetes-related retinopathy. The anti-cancer activity of the compounds may be related to their ability to antagonize cancer-related growth factors such as epidermal growth factor.
The compounds can be administered to a mammal, e.g., a human, in a dosage of 0.01 to 50 mg/kg/day, preferably 0.1 to 5 mg/kg/day.
Other embodiments are within the following claims.
|Cited Patent||Filing date||Publication date||Applicant||Title|
|US4282143 *||Jun 13, 1980||Aug 4, 1981||American Home Products Corporation||Octapeptides lowering growth hormone|
|US4291022 *||May 23, 1980||Sep 22, 1981||Sandoz Ltd.||Organic compounds|
|US4328135 *||Feb 12, 1981||May 4, 1982||American Home Products Corporation||Octapeptides lowering growth hormone|
|US4395403 *||Nov 16, 1981||Jul 26, 1983||Sandoz Ltd.||Polypeptides, processes for their production, pharmaceutical compositions comprising said polypeptides and their use|
|US4435385 *||Mar 2, 1982||Mar 6, 1984||Sandoz Ltd.||Antidiabetic, antiulcer, and antisecretory agent, and growth regulator|
|US4485101 *||Oct 11, 1983||Nov 27, 1984||Administrators Of The Tulane Educational Fund||Peptides|
|EP0029579A1 *||Nov 19, 1980||Jun 3, 1981||Sandoz Ag||Polypeptides, processes for their production, pharmaceutical compositions comprising said polypeptides and their use|
|EP0203031A2 *||Apr 15, 1986||Nov 26, 1986||The Administrators of The Tulane University Educational Fund||Biologically active lysine containing octapeptides|
|GB2095261A *|| ||Title not available|
|WO1986001516A1 *||Sep 4, 1985||Mar 13, 1986||Gibson Stephens Neuropharma||Cyclic polypeptides having mu-receptor specificity|
|1|| *||Cai et al., (Jul 1985), Proc. 9th Ann. Peptide, Symposium Abstract.|
|2|| *||Murphy et al., Chemical Abstracts, 104:28911x, (1986).|
|3|| *||Torres Alman, (Abstract), Chemical Abstracts, 102:160733, (1985).|
|4||Torres-Alman, (Abstract), Chemical Abstracts, 102:160733, (1985).|
|5|| *||Veber et al., (1984), Life Sciences 34 (14), 1371.|
|Citing Patent||Filing date||Publication date||Applicant||Title|
|US5147855 *||Jul 7, 1989||Sep 15, 1992||Yeda Research And Development Co. Ltd.||Modified vasoactive intestinal peptide|
|US5147856 *||Mar 28, 1989||Sep 15, 1992||Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R.A.S.)||Administering cyclic peptide prior to, during, and after surgery|
|US5225180 *||Sep 10, 1991||Jul 6, 1993||Diatech, Inc.||Technetium-99m labeled somatostatin-derived peptides for imaging|
|US5405597 *||Nov 17, 1992||Apr 11, 1995||Diatech, Inc.||Technetium-99m labeled somatostatin-derived peptides for imaging|
|US5443816 *||Feb 20, 1992||Aug 22, 1995||Rhomed Incorporated||Peptide-metal ion pharmaceutical preparation and method|
|US5447912 *||Aug 16, 1993||Sep 5, 1995||Senetek, Plc||Injecting the neuropeptides VIP and PHM and an adrenergic blocking agent|
|US5460785 *||Jan 3, 1992||Oct 24, 1995||Rhomed Incorporated||Direct labeling of antibodies and other protein with metal ions|
|US5504069 *||Feb 11, 1993||Apr 2, 1996||Biomeasure, Inc.||Inhibition of trauma-induced tumor growth|
|US5506339 *||Feb 21, 1992||Apr 9, 1996||The Administrators Of The Tulane Educational Fund||Octapeptide analogs of somatostatin having threonine at the sixth position|
|US5597894 *||Jun 5, 1995||Jan 28, 1997||The Louisiana State University Medical Center Foundation||Multi-tyrosinated somatostatin analogs|
|US5620675 *||Jul 21, 1993||Apr 15, 1997||Diatech, Inc.||Medical diagnosis|
|US5633263 *||Aug 15, 1994||May 27, 1997||The Administrators Of The Tulane Educational Fund||Linear somatostatin analogs|
|US5643549 *||Jan 11, 1994||Jul 1, 1997||Rhomed Incorporated||Leukostimulatory agent for in vivo leukocyte tagging|
|US5686418 *||Apr 8, 1996||Nov 11, 1997||Biomeasure Incorporated||Somatostatin|
|US5690905 *||May 31, 1995||Nov 25, 1997||Rhomed Incorporated||Peptide-metal ion pharmaceutical labeling method|
|US5708135 *||Dec 26, 1995||Jan 13, 1998||Biomeasure Incorporated||Cyclic peptide analogs of somatostatin|
|US5716596 *||Jun 23, 1992||Feb 10, 1998||Diatide, Inc.||Radioactively labeled somatostatin-derived peptides for imaging and therapeutic uses|
|US5759516 *||May 31, 1995||Jun 2, 1998||Rhomed Incorporated||Peptide-metal ion pharmaceutical preparation|
|US5783170 *||May 12, 1994||Jul 21, 1998||Diatide, Inc.||Peptide-metal chelate conjugates|
|US5814298 *||Jun 6, 1995||Sep 29, 1998||Diatide, Inc.||Radioactively labeled somatostatin-derived peptides for imaging and therapeutic uses|
|US5820845 *||Jun 6, 1995||Oct 13, 1998||Diatide, Inc.||Somatostatin-derived peptides for imaging and therapeutic uses|
|US5833942 *||Jun 6, 1995||Nov 10, 1998||Diatide, Inc.||Cyclic peptide derivatives of somatostatin; radiodiagnosis, therapy|
|US5843401 *||Jun 6, 1995||Dec 1, 1998||Diatide, Inc.||Radioactively labeled somatostatin-derived peptides for imaging and therapeutic uses|
|US5861139 *||Jun 5, 1995||Jan 19, 1999||Rhodes; Buck A.||Method and composition for labeling proteins, peptides and amino acids, including antibodies, with a variety of metals ions (tin), including radioisotopes|
|US5871711 *||Jun 23, 1993||Feb 16, 1999||Diatide, Inc.||Radioactively-labeled somatostatin-derived peptides for imaging and therapeutic uses|
|US5932189 *||Jul 29, 1994||Aug 3, 1999||Diatech, Inc.||Radiotherapy, radiodiagnosis peptides|
|US5968903 *||May 7, 1998||Oct 19, 1999||Biomeasure, Incorporated||Helicobacter and antigrowth agents, using somatostatin or agonist|
|US5981477 *||Mar 13, 1998||Nov 9, 1999||Diatide, Inc.||Peptide-metal chelate conjugates|
|US5985241 *||Mar 13, 1998||Nov 16, 1999||Diatide, Inc.||Diagnostic and radiodiagnostic agents, formed by reacting technetium-99m with a somatostatin receptor-binding peptide|
|US6001801 *||Jan 13, 1998||Dec 14, 1999||Biomeasure, Inc.||Administering antidiabetic agent cyclic peptide to inhibit insulin release in patient|
|US6004928 *||May 13, 1998||Dec 21, 1999||Biomeasure, Incorporated||Method of treating hyperlipidemia|
|US6017512 *||Sep 15, 1997||Jan 25, 2000||Diatide, Inc.||Cyclic hexapeptides not comprised of a disulfide bond covalently linked to a radiolabel e.g. technetium; scintigraphic imaging agents; radiodiagnosis and -therapy; antitumor,-carcinogenic and -diabetic agents; stability|
|US6051206 *||Jun 3, 1994||Apr 18, 2000||Diatide, Inc||Radiolabeled somatostatin-derived peptides for imaging and therapeutic uses|
|US6087337 *||Jul 9, 1993||Jul 11, 2000||Biomeasure Inc.||Treating melanomas or metastases of malignant melanomas by topically administering to mammal at the site of melanoma with a cyclic or linear octapeptide somatostatins|
|US6123916 *||Jun 13, 1994||Sep 26, 2000||Novartis Ag||For treating disorders with an aetiology comprising or associated with excess of gh-secretion|
|US6150333 *||Jul 26, 1999||Nov 21, 2000||Biomeasure, Inc.||Treatment of certain diseases and conditions such as gastroenterological diseases, crohn's disease, systemic sclerosis, external and internal pancreatic pseudocysts and ascites, vipoma, nesidoblastosis, hyperinsulinism|
|US6160184 *||Aug 5, 1997||Dec 12, 2000||The Regents Of The University Of California||A chemical intermediate for forming a drug treating cancer|
|US6241965||Jul 21, 1994||Jun 5, 2001||Diatide, Inc.||Somatostatin derivatives and their radiolabelled products|
|US6252093||Oct 5, 2000||Jun 26, 2001||The Regents Of The University Of California||Total synthesis of antitumor acylfulvenes|
|US6262229||May 13, 1997||Jul 17, 2001||Biomeasure Incorporated||Octapeptides|
|US6323181||Aug 31, 1999||Nov 27, 2001||The Regents Of The University Of California||Antitumor agents|
|US6380403||Feb 9, 2000||Apr 30, 2002||Regents Of The University Of California||Illudin analogs useful as antitumor agents|
|US6469184||Jun 5, 2001||Oct 22, 2002||Regents Of The University Of California||Coupling a cyclopentenone with a cyclic carbonyl ylide dipole|
|US6548679||Aug 17, 2000||Apr 15, 2003||The Regents Of The University Of California||Antitumor agents|
|US6639105||Apr 29, 2002||Oct 28, 2003||The Regents Of The University Of California||For inhibiting tumor cell growth|
|US6703481||Sep 26, 2000||Mar 9, 2004||The Administration Of The Tulane Educational Fund||Somatostatin antagonists|
|US6717017||Aug 30, 2002||Apr 6, 2004||The Regents Of The University Of California||4'-alkyl,6'-(protected hydroxy),7'-hydroxy-spiro(cyclopropane-1,5'-hexahydroindan-2,3 a(4),7a(1)-triene) compound of given formula, intermediate to illudin analogs of the mushroom omphalotus illudens|
|US6787521||Jan 16, 2001||Sep 7, 2004||Societe De Conseils De Recherches Et D'applications Scientifiques, S.A.S.||Skin disorders; kidney and liver disorders|
|US6806363||Oct 16, 2000||Oct 19, 2004||Mayo Foundation For Medical Education & Research||Drugs for diagnosis/therapy; radionuclide-based tumor imaging|
|US6838073||Oct 16, 2000||Jan 4, 2005||Mayo Foundation For Medical Education And Research||Cobalamin conjugates useful as imaging and therapeutic agents|
|US6855696||Nov 5, 2001||Feb 15, 2005||The Regents Of The University Of California||Antitumor agents|
|US6908918||Apr 14, 2003||Jun 21, 2005||Regents Of The University Of California||Ketone spirocyclopropaneindene compounds; antineoplastic agents to inhibit tumor cell growth in vitro or in vivo; particularly effective against solid tumors and multi-drug resistant tumors|
|US6987193||Oct 27, 2003||Jan 17, 2006||The Regents Of The University Of California||Illudin analogs useful as antitumor agents|
|US7026289||May 13, 1998||Apr 11, 2006||Societe De Conseils De Recherches Et D'applications Scientifiques, Sas||Method and compositions for treating hyperlipidemia and other conditions|
|US7034003||May 13, 1998||Apr 25, 2006||Societe De Conseils De Recherches Et D'applications Scientifiques, Sas||Somatostatin and somatostatin agonists for decreasing body weight|
|US7094753 *||Nov 21, 2002||Aug 22, 2006||Societe De Conseils De Recherches Et D'applications Scientifiques, Sas||Somatostatin analog and uses thereof|
|US7122622 *||Apr 16, 2003||Oct 17, 2006||Biosynthema Inc.||Somatostatin analogue as peptide and chelating group covalently linked to N-terminal free amino group of peptide, wherein analogue carries 1-naphthylalanine or 3-benzothienylalanine residue in 3-position; diagnosis|
|US7141603||Jun 13, 2005||Nov 28, 2006||The Regents Of The University California||Ketospirocyclopropaneindene compounds; anticarcinogenic agents|
|US7179445||Feb 24, 2004||Feb 20, 2007||Mayo Foundation For Medical Education And Research||Cobalamin conjugates useful as imaging and therapeutic agents|
|US7232829||Apr 6, 2001||Jun 19, 2007||Regents Of The University Of Minnesota||Analgesics; anticonvulsants; hypotensive agents; brain damage; antiarrhythmia agents; opioid receptors|
|US7238666||Sep 7, 2004||Jul 3, 2007||Societe De Conseils De Recherches Et D'applications Scientifiques, S.A.S||Method of inhibiting fibrosis with a somatostatin agonist|
|US7256174||Feb 18, 2003||Aug 14, 2007||Societe De Conseils De Recherches Et D'applications Scientifiques, S.A.S.||Administering a therapeutically effective amount of H-Cys-Phe-Phe-D-Trp-Lys-Thr-Phe-Cys-NH2, wherein a disulfide bond exists between the free thiols of two cysteine residue|
|US7329759||Dec 20, 2005||Feb 12, 2008||The Regents Of The University Of California||1-Substituted-[1H-indene-6,1'-cyclopropane]-4-one derivatives: solid tumors and multi-drug resistant tumors; may also be targeted to a particular tumor; can either be cytostatic or cytotoxic to the tumor cells|
|US7411031||May 18, 2004||Aug 12, 2008||Rutgers, The State University Of New Jersey||Synthesis of polyanhydrides|
|US7468432||Feb 12, 2004||Dec 23, 2008||Mayo Foundation For Medical Education And Research||Cobalamin conjugates useful as antitumor agents|
|US7531162||Feb 13, 2006||May 12, 2009||Mayo Foundation For Medical Education And Research||Transcobalamin receptor binding conjugates useful for treating abnormal cellular proliferation|
|US7550423||Nov 13, 2003||Jun 23, 2009||The Administrators Of The Tulane Educational Fund||Modulate hormone release; controlling neurotransmitter release|
|US7591995||Oct 31, 2006||Sep 22, 2009||Mayo Foundation For Medical Education And Research||Cobalamin conjugates useful as imaging and therapeutic agents|
|US7629380||Nov 16, 2006||Dec 8, 2009||The Regents Of The University Of California||Antitumor agents|
|US7655695||Aug 3, 2006||Feb 2, 2010||The Regents Of The University Of California||N-hydroxy-N-(methylacylfulvene)urea; solid tumor in a lung, ovarian, prostate, breast, endometrial, bladder, renal, pancreatic, central nervous system, melanoma, colon carcinoma or hematologic cancer; leukemia|
|US7662784||Nov 29, 2005||Feb 16, 2010||Ipsen Pharma, S.A.S.||Method for decreasing body weight using a somatostatin receptor agonist|
|US7713939||Dec 12, 2007||May 11, 2010||The Regents Of The University Of California||1-Substituted-[1H-indene-6,1'-cyclopropane]-4-one derivatives: solid tumors and multi-drug resistant tumors; -cell leukemia, B-cell lymphoma, myeloma, T-cell leukemia, T-cell lymphoma, small leukemia, and small cell lymphoma|
|US8142764||Feb 25, 2009||Mar 27, 2012||University Of Louisville Research Foundation||Synthetic biofilm-inhibiting peptides|
|US8173148||Nov 10, 2005||May 8, 2012||Tolmar Therapeutics, Inc.||Stabilized polymeric delivery system comprising a water-insoluble polymer and an organic liquid|
|US8192719||Feb 19, 2007||Jun 5, 2012||Aeterna Zentaris Gmbh||Methods and kits to diagnose growth hormone deficiency by oral administration of EP 1572 or EP 1573 compounds|
|US8313763||Feb 15, 2007||Nov 20, 2012||Tolmar Therapeutics, Inc.||Sustained delivery formulations of rapamycin compounds|
|US8569449||May 8, 2008||Oct 29, 2013||University Of Louisville Research Foundation, Inc.||Synthetic peptides and peptide mimetics|
|US8765969||Jul 3, 2008||Jul 1, 2014||Promega Corporation||Luminescence-based methods and probes for measuring cytochrome P450 activity|
|EP0542934A1 *||Feb 7, 1992||May 26, 1993||Biomeasure, Inc.||Method of treating benign and malignant proliferative skin disease|
|EP1291022A1 *||Sep 5, 2002||Mar 12, 2003||Societe De Conseils De Recherches Et D'applications Scientifiques S.A.S.||Methods of using lanreotide, a somatostatin analogue|
|EP1935986A2||May 31, 2006||Jun 25, 2008||Promega Corporation||Luminogenic and fluorogenic compounds and methods to detect molecules or conditions|
|EP2062914A2||Jun 7, 2002||May 27, 2009||Ipsen Pharma||Somatostatin-dopamine chimeric analogs|
|EP2161037A2||Apr 21, 2004||Mar 10, 2010||Ipsen Pharma||Camptothecin-Somatostatin conjugates|
|EP2233155A2||Jul 27, 2001||Sep 29, 2010||Rutgers, The State University of New Jersey||Therapeutic polyanhydride compounds for drug delivery|
|EP2272972A1||May 31, 2006||Jan 12, 2011||Promega Corporation||Luminogenic and fluorogenic compounds and methods to detect molecules or conditions|
|EP2272973A1||May 31, 2006||Jan 12, 2011||Promega Corporation||Luminogenic and fluorogenic compounds and methods to detect molecules or conditions|
|EP2277549A2||Jul 27, 2001||Jan 26, 2011||Rutgers, The State University of New Jersey||Therapeutic polyanhydride compounds for drug delivery|
|EP2277872A1||May 31, 2006||Jan 26, 2011||Promega Corporation||Luminogenic and fluorogenic compounds and methods to detect molecules or conditions|
|EP2341134A2||Jan 30, 2004||Jul 6, 2011||Promega Corporation||Covalent tethering of functional groups to proteins|
|EP2369006A1||Jan 30, 2004||Sep 28, 2011||Promega Corporation||Covalent tethering of functional groups to proteins|
|EP2395078A2||Jul 29, 2005||Dec 14, 2011||Promega Corporation||Covalent tethering of functional groups to proteins and substrates therefor|
|EP2395358A2||Jul 29, 2005||Dec 14, 2011||Promega Corporation||Covalent tethering of functional groups to proteins and substrates therefor|
|EP2455457A2||Jan 30, 2004||May 23, 2012||Promega Corporation||Covalent tethering of functional groups to proteins|
|EP2455458A2||Jan 30, 2004||May 23, 2012||Promega Corporation||Covalent tethering of functional groups to proteins|
|EP2492342A1||Oct 30, 2007||Aug 29, 2012||Promega Corporation||Mutant hydrolase proteins with enhanced kinetics and functional expression|
|EP2626703A1||Mar 26, 2009||Aug 14, 2013||Promega Corporation||Protein labeling with cyanobenzothiazole conjugates|
|EP2662087A1||Apr 21, 2004||Nov 13, 2013||Ipsen Pharma||Somatostatin vectors|
|EP2664343A2||Nov 17, 2009||Nov 20, 2013||Syntaxin Limited||Suppression of cancer|
|EP2778234A1||May 31, 2006||Sep 17, 2014||Promega Corporation||Luminogenic and fluorogenic compounds and methods to detect molecules or conditions|
|WO1991009056A1 *||Dec 4, 1990||Jun 27, 1991||Univ Tulane||Octapeptide analogs of somatostatin having threonine at the sixth position|
|WO1992013554A1 *||Feb 7, 1992||Aug 20, 1992||Biomeasure Inc||Method of treating benign and malignant proliferative skin disease|
|WO1998024807A2 *||Dec 4, 1997||Jun 11, 1998||Admin Tulane Education Fund||Somatostatin antagonists|
|WO2000006185A2 *||Jul 29, 1999||Feb 10, 2000||Biomeasure Inc||Methods of using lanreotide, a somatostatin analogue|
|WO2003065928A2||Feb 6, 2003||Aug 14, 2003||Kathryn E Uhrich||Therapeutic polyesters and polyamides|
|WO2006093529A2||Jul 29, 2005||Sep 8, 2006||Promega Corp||Covalent tethering of functional groups to proteins and substrates therefor|
|WO2009123713A1||Apr 1, 2009||Oct 8, 2009||Cornell University||Organo-soluble chitosan salts and chitosan-derived biomaterials prepared thereof|
|WO2011077086A2||Dec 21, 2010||Jun 30, 2011||Ucl Business Plc||Agents having tissue generative activity|
|WO2011112966A1||Mar 11, 2011||Sep 15, 2011||Promega Corporation||Bioluminescent assays using cyanobenzothiazole compounds|
|WO2013033345A1||Aug 30, 2012||Mar 7, 2013||Regents Of The University Of Minnesota||Immunomodulators and immunomodulator conjugates|
|WO2013109939A1||Jan 18, 2013||Jul 25, 2013||Regents Of The University Of Minnesota||Methods of making and using nanostructures|
| || |
|U.S. Classification||514/5.9, 930/23, 930/160, 514/806, 930/21, 530/311, 930/20, 930/DIG.802, 514/11.3, 514/11.7, 514/11.4|
|International Classification||A61K38/00, C07K14/655|
|Cooperative Classification||Y10S514/806, Y10S930/16, C07K14/6555, A61K38/00|
|Apr 18, 2008||AS||Assignment|
Owner name: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF
Free format text: EXECUTIVE ORDER 9424, CONFIRMATORY LICENSE;ASSIGNOR:TULANE SCHOOL PUBLIC HLTH/TROP MEDICINE;REEL/FRAME:020826/0840
Effective date: 19930816
|Jan 30, 2001||FPAY||Fee payment|
Year of fee payment: 12
|Dec 4, 1996||FPAY||Fee payment|
Year of fee payment: 8
|Feb 1, 1993||FPAY||Fee payment|
Year of fee payment: 4
|Aug 14, 1990||CC||Certificate of correction|
|Jun 22, 1988||AS||Assignment|
Owner name: THE ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND,
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNORS:MURPHY, WILLIAM A.;COY, DAVID H.;HEIMAN, MARK L.;REEL/FRAME:004925/0010
Effective date: 19880615
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:MURPHY, WILLIAM A.;COY, DAVID H.;HEIMAN, MARK L.;REEL/FRAME:004925/0010